Acylmercapto-alkylamines and process for the manufacture thereof



United States Patent 9 ACYLMERCAPTO-ALKYLAMINES AND PROCESS FOR THE MANUFACTURE THEREQF Robert Schwyzer, Riehen, Switzerland, assignor to Ciha Pharmaceutical Products, Inc, Summit, N. J.

No Drawing. Application June 23, 1953, Serial No. 363,649

Claims priority, application Switzerland July 3, 1952 4 Claims. (Cl. 260-455) The present invention relates to a process for the manufacture of N:S-diacyl-mercapto-alkylamines which can be represented by the general formula in which R represents the residue of an acid, e. g., an aliphatic or cyclic, e. g., aromatic or heterocyclic carboxylic acid acyl or sulphonic acid acyl, and R1 represents a carboxylic acid acyl. R and R1 are, for example, more particularly the residues of acetic acid, propionic acid, dichloracetic acid, succinic acid, pantothenic acid, benzoic acid, nicotinic acid or isonicotinic acid. The alkylene residue may be a straight or branced chain. Advantageously it is an ethylene residue.

The present invention also embraces new NzS-diacylmercapto-alkylamines of the formula in which R2 represents a sulphonic acid acyl, a cyclic carboxylic acid acyl or an aliphatic carboxylic acid acyl having at least 6 carbon atoms and R3 represents a carboxylic acid acyl.

Of special importance are alkylamines of Formula II in which R2 represents the pantothenyl radical which can be represented by the formula and R3 represents carboxylic acid acyl.

The compounds of the invention are useful as medicaments or as intermediate products, e. g., for the manufacture of medicaments. More particularly, compounds of the present invention are useful as metabolites. Thus N-pantothenyl-S-benzoyl--mercapto ethylamine which, unlike pantetheine, crystallizes readily and melts at 116 C., promotes equally well the growth of, e. g., the lactic acid bacteria Lactobacillus helveticus and Lactobacillus bulgaricus.

The compounds obtainable by the instant process are also of outstanding importance because the acyl attached to the sulphur atom can easily be split ofi selectively. Furthermore, the compounds are especially suited for the introduction of acyl radicals into compounds containing active hydrogen. The selective deacylation can be carried out with a compound containing active hydrogen, for example, it is advantageously brought about with ammonia or a compound containing amino groups such as an amine, an amino-carboxylic acid or a hydroxylamine. Unexpectedly the corresponding acid amide is formed in addition to the mercapto-compound. The deacylation may, however, be carried out with a compound containing active hydrogen in the form of hy- I droxyl groups, such as water or an alcohol.

The process of the present invention comprises reacting an N-acyl-alkylene-imine with a thiocarboxylic acid. Thereaction may be carried out in the presence of an organic diluent, such as ether, benzene, toluene,

dirnethylformamide or in the presence of water. It takes 2,785,191 Patented Mar. 12, 1957 place at low temperatures, and it is of advantage to work at room temperature.

The reaction may be represented by the following equation starting, for example, from an N-acyl-alkyleneimine and deacylating, for example, with an amino-compound:

R and R in the above equations have the same meaning as hereinabove indicated, and RR"NH stands for an amine. The N-acyl-alkylene-imines can be prepared by a new process which is also embraced within the present invention. The novel process comprises reacting an anhydride of a carbonic acid semi-ester and an organic acid with an alkyleneimine in the presence of an acidbinding agent, for example, a tertiary amine. The reaction can be represented by the following equation:

wherein R has the same meaning as defined above.

The following examples illustrate the invention, the parts being by weight unless otherwise stated, and the relationship of parts by weight to parts by volume being the same as that of the gram to the cubic centimeter:

Example 1 20 parts of thioacetic acid are stirred into a solution of 20 parts of N-acetyl-ethylene-imine in parts by volume of benzene at 05 C. After /2 hour at room temperature, the solvent is removed and the residue is subjected to distillation in vacuo. At 165 C. under 10 mm. pressure of mercury 26.2 parts (=72 percent of the theoretical yield) of N:S-diacetyl-B-mercapto-ethylamine of the formula distil over. After a further distillation the product is pure and melts at 28 C.

By shaking enough of the compound to cover the tip of a spatula with a small crystal of hydroxylamine hydrochloride for a short time at room temperature with water and l N-solution of caustic soda, and pouring the whole into a solution of a small amount of F6Cl3 mixed with an excess of hydrochloric acid, the characteristic red coloration of acetyl-hydroxamic acid (CH3CO.NHOH) is produced immediately.

By dissolving a test portion of the compound in water, mixing it with two drops of sodium nitroprusside solution of 1 percent strength and two drops of a 1 N-solution of ammonia, there is produced after a short initial period an increasing blue-red coloration, which increases as N- acetyl-fi-mercapto-ethylamine is liberated by the ammonia.

By maintaining 1 part of NzS-diacetyl-mercaptoethylamine with 1 part of aniline in 100 parts by volume of water (pH=3) for 48 hours at room temperature, 0.25 part of acetanilide (CsHsNH'COCHs), melting at 114 C., can be isolated at the endof this period by After maintaining 1.6 parts of NzS-diacctyl-B-mercapto-ethylamine with 0.75 part of glycine. in 2 parts by volume of0.5-n sodium hydroxide solution for 48 hours 5' .N 1 at 20 C., 0.45 part of N-acetyl-glycine (=38.5% of V the theoretical amount) can be isolated on evaporation of the solvent and acidification with dilute hydrochloric l acid, melting at 206 C. 7

By meansJ of an anaogouls rlnixture ising ldpart of 10 Emmplev 4 ara-aminoenzolc 2101 an art 0 l :ciacety ihercaptoethylamine there is obtair i ed 0.5 part of crystal 18 Writs OI (+)"ca1c,mm'p antothaliate dissolved line para-acetylarninobenzoic acid in a pure form melting m 10 pans by 9; water d i d 9?? at C. a v by volume of triethylamme The calcium is prec1p1tated Example 2 by means of an exactly equwalent quant ty of an aqueous V oxalic-acid solution- Afterfiltering and evaporation of 7 I11 exactly the manner as described 111 E p 1 the solvent there remain 12.5 parts of syrupy triethylin the 0f y fip f f y there ammonium-pantothenate. The compound is dissolved in are obtained from 10 parts of N-acetyl-ethylenemme and .25 parts by volume f dry dim th lf mid and 20 Paris 05111101363201? 361d, 20 Paris 20 cooled to 5 C. At this temperature, 4.1 parts of ethyl y y f p y the formula chloroformate, dissolved in 20 parts by volume of ethyl ,CH3 CO .NH CH2 CH2 S CO;C6H5 acetate, are stirred in dropwise. After 10 minutes the o resulting mixture, without first separating the triethylamf at 87 monium chloride which has precipitated, is rapidly added This comppund reacts with NHzoHganfl ammo in portions While stirring to a solution, cooled to 5 C., compounds In a .manner analogous to of 2 parts of ethylene-imine and 5 parts of triethylamine mercapto'ethylamme' in 50 parts by volume of ethyl acetate. After 20 minutes Example 3 the resulting mixture is poured into acoldsolution of 7 1.23 parts of nicotinic acid are dissolved in dimethylparts of thiobenzoic acid in 100 parts by volume of ethyl 'formamide and the solution is mixed with 1.01 parts of acetate. The mixture is allowed to stand for 30 minutes triethylamine. "1.08 parts of ethyl chloroformate disat 0 C., filtered and freed from. solvent at a low tem .solved in ethyl acetate are then added, 'while stirring, at. perature, first in a vacuumproduced by a water jet 0 C. After 10 minutes the mixture is filtered to separate pump, then under a high vacuum (0.05 mm. pressure of the precipitated triethylammonium chloride, and the Q mercury). The residue is dissolved in 1000 parts by filtrate, containing the anhydride of 'nicotinic acid and volume of Water and extracted for the first time with ethoxy-formic acid, is introduced dropwise into a mixture ether (three times 500 partsby volume). The N-pantoof 0.460 part of ethylcne-imine and 1.1 parts 'of triethylthenyl-S-benzoyl-B-mercapto-ethylamine [(+)-S-benzoylamine in ethyl acetate at 0 C. After /2 hour N- pantetheine] of the formula CH: 7 HOCHs-C-CHOH-OONH-CHzCHiCONHCH:CHrSOO- nicotinyl-ethylene-imine and trimethyl-ammoniurn is isolated by extracting the aqueous phase with ethyl ethoxy-forrnate are formed. acetate (5 times 500 parts by volume) and purified by in order to prepare N-nicotinyl-S-benzoyl-mercaptocrystallization from dry ethyl acetate. The yield is 8 ethylamine, 1.5 parts of thiobenzoic acid are added to parts and the melting point is at 116 C. On drying the solution, which contains N-nicotinyl-ethylene-imine. With sodium sulphate and keeping in a'refrigerator (at The mixture is freed from solvent in vacuo and the -l0 C.) the ethereal extracts form ,a deposit of a residue is taken up in benzene and Washed with a 2 N- further quantity of the crystalline compound, For solution of sodium carbonate and with water. By eva analyzing, the substance is recrystallized three times from crating the benzene solution, there is obtained a total of ethyl acetate and dried for 5 hours at 60 C. under a 2.3 parts of crystalline N-nicotinyl-S-benzoyl-B-mercapto- Pressure of of y- Colorless t needles ethylamine, corresponding to 82 percent of the theoretical melting at are Obtained; the Specific rotation i yield calculated on the nicctinic acid; BY recrystalliza- 41) P 0 1:1, in ethanol) 7 tion from almixture of benzene and other there are obm 5 3 i16- Z'C :ELS e' t l his su bstiiri ce capii blef tii infr odiiing the S-a'cyl In exactly the Same manner as discnbed m Example 4 ouo nto co n ounds containin active hydro n in a m ihe case of Nipalitotheny1 Sbenzoimfi mercaptoethyl' =5 a amine, 4.7 parts of triethylammoniumpantothenate are resirnrlar manner. to toe compounds descrlbed 1n Examples acted, but the thiobenzoic acid is replaced by an excess 1 3 of thioacetic acid. Working up is carried out by taking Tug g s desFnbed abova may be repmsemed by up the reaction product, after it has been freed from the the followmg equations: solvents, .in 200 parts by volume of water half saturated with sodium chloride, extracting with ether and isolating CO CO OC9H5 CH1 7 the '(+)-S-acetyl-pantetheine by agitation 5 times with EN l M02115), 200 parts by volume of ethyl acetate (+10 percent metha- CH2 7 n01) each time. The combined extracts are washed with 50 parts by volume of half saturated sodium chloride CH7 solution, dried with sodium sulphate and'evaporated under a vacuum produced by a water jet pump. The colorless l (VJZHSO'GO'OH'NWQHW residue Weighs 4 parts. It is chromatographed'in ethyl acetate over 120 parts of neutral alumina of activity IV.

Six fractions, each of parts of ethyl acetate; eluate 2.3

0.00604 part of N-pantothenyl-S-acetyl ,8 mercaptoethyIamine+O.5 part by volume of methanol-$1.0 part by volume of NHzOH solution-H part by volume of acetate butler (pH=5.4) are allowed to stand at room temperature for 15 minutes, then mixed with 1.0 part by volume of HCl solution, 1.0 part by volume of FeCla solution and 5.0 parts by volume of water. The intensity of the color produced is determined in the Lumetronecolorimeter. The transmission is 38.7% at e=1 cm.; \=515 [1112.

The intensity of the color produced by 000616 part N-pantothenyl-S-benzoyl ,6 mercapto-ethylamine, after undergoing exactly the same treatment, is exactly the same.

By reacting N-pantothenyl-S-benzoyl- S-mercaptoethylamine with ammonia the following result is obtained:

(a) With aqueous amm0nia.-0.l00 part of (+)-S- benzoylpantetheine are dissolved in 2 parts by volume of methanol and made up to 5 parts by volume with concentrated NHz water (1:1). After 1, 6, 16 and 31 minutes at room temperature of 28 C., 1.0 part by volume of the liquid is pipetted into 9 parts by volume of 0.01-N iodine solution (in glacial acetic acid) and titrated back with 0.01-N thiosulfate to determine the amount of the mercapto compound produced.

0.200 part of N-pantothenyl-S-benzoyl B mercaptoethylamine, reacted in the same way with ammonia (during 40 minutes), after agitation with ethyl acetate, dissolution of the extract in water, treatment with animal charcoal and extraction with ethyl acetate, yields 0.060 part (=90 percent of the calculated quantity) of crystalline benzamide. After recrystallization from benzene the product melts at 125 C. and shows no depression of the mixed melting point with a comparative preparation of melting point 125 C.

(b) With methanolic amm0nia.0.020 part of N-pantothenyl-S-benzoyl-fi-mercaptoethylamine is dissolved in 1 part by volume of methanol saturated with NH3. After 2 hours S-benzoyl groups can no longer be detected with hydroxylamine and FeCls. The product is chromatographed over Whatman paper No. 1 with a mixture of butanol, water and glacial acetic acid 4:5 :1 at 28 C., dried for 5 minutes at C., sprayed with 2% sodium nitroprussiate, then with 2-N KCN.

Ammonolysis:

2 hours: 1 spot Rr=0.75 24 hours: 1 spot RF=0.75 +s1nall spot Rr=0.47

The RF value of the resulting substance corresponds to that of pantetheine under identical conditions; the product of further degradation (RF-=0-47) has not been investigated.

N-pantothenyl-S-acetyl-fl-mercapto ethylamine, when treated in an analogous manner with methanolic ammonia, becomes degraded to pantetheine.

By reaction of N-pantothenyl-S-benzoyl-B-mercaptoethylamine with an alcohol, such as methanol, the corresponding benzoic acid esters can be obtained:

0.100 part of N-pantothenyLS-benzoyl-fl-mercaptoethylamine is boiled with 3 parts by volume of methanol and 0.005 part of (anhydrous)sodium acetate for 5 hours. The whole is then mixed with 10 parts by volume of ether and the mixture thoroughly washed with water. The ethereal layer is dried with sodium sulphate and evaporated. The residue is distilled in a test tube under reduced pressure, benzoic acid-methyl ester being obtained in good yield.

0.36 part of N-(+)-pantothenyl-S-benzoyl-fi-mercaptoethylamine are mixed with 1 part by volume of sodium glycinate solution and the mixture maintained at 3540 C. for 12 hours. The mercapto compounds which has formed is then removed with ethyl acetate and the ethyl acetate extract washed with water. The aqueous portions are combined and evaporated down to a small volume. After mixing with 1 part by volume of l-N HCl the hippuric acid formed begins to crystallize. Its melting point is at C.

Example 6 0.9 part of N-para-toluene 'sulphonyl-ethylene-imine is dissolved in 8 parts by volume of ethyl acetate together with the thiolbenzoic acid prepared from 0.9 part of potassium salt of thiolbenzoic acid by acidifying with hydrochloric acid. The solution is boiled for 2 hours under reflux. Before cooling, 4 parts by volume of petroleum ether are added. Overnight 1.3 parts of N-para-toluenesulfonyl-S-benzoyl-fi-mercapto-ethyl-amine separate in theform of large flat crystals up to 1 cm. in length. It melts at Ill-112 C.

The reaction is illustrated by the equation 

1. N-PANTOTHENYL-S-BENZOYL-B-MERCAPTO-ETHYLAMINE.
 4. A PROCESS FOR THE MANUFACTURE OF MERCAPTO-ETHYLAMIDES WHICH COMPRISES REACTING AN N-ACYL-ETHYLENE-AMINE, WHEREIN THE ACYL RADICAL IS THAT OF AN ACID SELECTED FROM THE GROUP CONSISTING OF SATURATED LOWER ALKYL CARBOXYLIC ACIDS, DICHLORACETIC ACID, SUCCINIC ACID, PANTOTHENIC ACID, BENZOIC ACID, NICOTINIC ACID, ISONICOTINIC ACID AND P-TOLUENE SULFONIC ACID, WITH AN ACID SELECTED FROM THE GROUP CONSISTING OF SATURATED LOWER ALIPHATIC THIOCARBOXYLIC ACIDS AND BENZENE THIOCARBOXYLIC ACIDS. 